Targeting high-risk HPV oncoproteins: Emerging therapeutic strategies and translational challenges

Abstract

Persistent infection with high-risk human papillomavirus (HPV) is a major cause of cervical and other anogenital and oropharyngeal cancers. The viral oncoproteins E6 and E7 promote malignant transformation through disruption of tumor-suppressor pathways, making them attractive targets for therapeutic intervention. However, the development of effective oncoprotein-directed treatments remains challenging because of their intracellular localization, complex interactions with host proteins, and the difficulty of selectively inhibiting viral functions without affecting normal cellular processes. Emerging approaches include small-molecule inhibitors, gene silencing, genome editing, targeted protein degradation and therapeutic immunotherapy. Although several strategies have demonstrated promising preclinical activity, their clinical applicability remains limited by delivery challenges, off-target effects, tumor heterogeneity and insufficient evidence of durable efficacy. This mini review examines the principal therapeutic approaches targeting high-risk HPV oncoproteins, highlights barriers to clinical translation and discusses opportunities for integrating structural biology, computational drug discovery and experimental validation to accelerate the development of targeted treatments.